What is disclosed is a device for repairing and replacing lost or damaged tissue. Particularly, one embodiment is directed to a multi-phasic prosthetic device for repairing or replacing cartilage or cartilage-like tissues. Said prosthetic devices are useful as articular cartilage substitution material and as a scaffold for regeneration of articular cartilaginous tissues.
Cartilage is found throughout the body, such as in the supporting structure of the nose, ears, ribs (elastic cartilage), within the meniscus (fibrous cartilage), and on the surfaces of joints (hyaline cartilage or articular cartilage). A joint is a bending point where two bones meet. The knee, hip, and shoulder are the three largest joints.
The specialized covering on the ends of bones that meet to form an articulating joint is called hyaline or articular cartilage. It is the cartilage that is damaged and wears as one ages, or sustains an injury. Articular cartilage is unique amongst the body tissues in that it has no nerves or blood supply. This means that damage will not be felt until the covering wears down to bare underlying bone. Bone is very sensitive and the sharp pain of arthritis often comes from irritation of bone nerve endings and since human tissue has a very limited capacity to heal without a blood supply, articular cartilage cannot repair itself effectively.
Articular cartilage tissue covers the ends of all bones that form diarthrodial joints. The resilient tissues provide the important characteristic of friction, lubrication, and wear in a joint. Furthermore, it acts as a shock absorber, distributing the load to the bones below. Without articular cartilage, stress and friction would occur to the extent that the joint would not permit motion. As stated above, articular cartilage has only a very limited capacity to regenerate. If this tissue is damaged or lost by traumatic events, or by chronic and progressive degeneration, it usually leads to painful arthrosis and decreased range of joint motion.
Articular cartilage repair following injury or degeneration represents a major clinical problem, with treatment modalities being limited and joint replacement being regarded as appropriate only for the older patient.
Current treatments for articular cartilage damage are varied and include anti-inflammatory medication, viscosupplementation, arthroscopic chondroplasty, autogenous articular cell implantation, microfracture and osteochondral articular transplantation.
Anti-Inflammatory Medication:
Aspirin was the first anti-inflammatory medication in the world. This was followed in 1950 by cortisone (steroidal medication) used orally or by injection. (Extensive use of cortisone not only has a wide variety of harmful effects, but is also believed to harm cartilage.) Later the non-steroidal drugs such as Motrin came along. These were safer than Aspirin and cortisone but had potent side effects, especially causing bleeding within the stomach and intestinal ulcers. These complications led to the development of the COX-2 inhibitor drugs, Celebrex and Vioxx. While much safer and seemingly more effective, Vioxx was found to have significant cardiac side effects and is no longer available. With certain precautions, Celebrex is still widely used. However, these anti-inflammatory medications only treat the symptoms of cartilage damage and arthritis and do not promote repair.
Viscosupplementation:
Viscosupplementation is a procedure that involves the injection of gel-like substances (hyaluronates) into a joint to supplement the viscous properties of synoval fluid. Currently, hyaluronate injections are approved for the treatments of osteoarthritis of the knee in those who have failed to respond to more conservative therapy. Once again, this procedure only treats the symptoms of cartilage damage and arthritis and does not promote repair.
Arthroscopic Chondroplasty:
Chondroplasty is a term referring to the arthroscopic smoothing of unstable articular surfaces either with mechanical shaving or thermal devices. While not a restorative measure, so called debridement can be useful in reducing irritating cartilage debris that breaks off in the joint or causes catching or grinding sensations. The resulting improvement in the control of inflammation can last for several years. But this is not a final solution as the degenerative process continues to wear away at the articular cartilage.
Autogenous Articular Cell Implantation (ACI):
Autogenous cell implantation can be used for large, shallow defects, which do not involve the subchondral bone. In this procedure, cartilage cells collected from the patient and grown to many millions through cell culture techniques are injected into the joint, under a membrane that has been attached to the cartilage surface. Although successful, the window of opportunity for this procedure is often missed, as the few clinical symptoms showing the need for this treatment are not evident until the defect deepens to involve the underlying bone, thus the damage encountered upon detection is frequently too extensive for repair through ACI.
Microfracture:
The goal of this arthroscopic technique is to improve the blood supply to the bare areas of the joint by creating tiny perforations in the underlying bone. The resulting bone marrow bleeding carries powerful growth stimulating factors found in platelets as well as stem cells to the damaged area creating what is referred to as a super-clot. Healing and repair follow over several weeks. Studies have shown that microfracture techniques do not fill in the chondral defect fully and the repair material formed is fibrocartilage. The fibrocartilage tissue can temporarily return function for activities such as running and a sport play, but ultimately fails, as fibrocartilage is unable to mechanically share and disipate loading forces as effectively as the original hyaline cartilage. Fibrocartilage is much denser and isn't able to withstand the demands of everyday activities as well as hyaline cartilage and is therefore at higher risk of breaking down.
Osteochondral Articular Transplantation:
Osteochondral transplantation (i.e. mosaioplasty) involves transportation of tissue plugs from one location of the knee to another. Special instrumentation has been devised to harvest plugs of articular cartilage and its supporting bone from the patient's own joint. The harvested tissue is then transported to the damaged site where it is inserted into prepared holes. Several plugs can fill up rather larger defects and will grow to re-supply a new joint surface. Unfortunately, this procedure leaves defects of equal or worse proportions elsewhere and often the harvested tissue is not viable due to the traumatic harvesting procedure.
Due to the problems associated with current state of the art treatments, much work has been done to produce a synthetic off-the-shelf scaffold to be used in place of the harvested osteochondral plug.
Originally, single-phase scaffolds of uniform construction were contemplated for use as implants. However, these single-phase scaffold implants proved unsuccessful in healing of the complex multiphasic articular cartilage along with the underlying bone. Soon biphasic and then gradient devices were developed that were either mechanically or anatomically specific for the tissues involved. While these showed an improvement over single phase devices, it is evident that these devices do not take into consideration how cells will be migrating into the scaffolds as well as how their presence influences the surrounding, uninvolved tissue. Additionally, prior art scaffolds did not take into consideration the joint fluid and how it impacts maturation and maintenance of healthy hyaline cartilage. Although prior art synthetic scaffolds, whether single phase, multi-phase, or of gradient construction have proven suitable for growth and maturation of cells within a bioreactor, these prior art devices are unsuitable for direct implantation, for at least the reasons that follow.
Applicants have made the surprising discovery that in effecting the repair of cartilage defects, prior art synthetic implants and synthetic bi-phasic implant devices failed to recognized the need to ignore the normal histological and mechanical gradient of the articular cartilage, and instead focused on the limited cell population surrounding the defect and its slow rate of tissue formation within the devices resulting from this sparse population of cells. The prior art synthetic implants mistakenly focused on speeding up the rate of cell migration within the scaffold in hopes of getting tissue to form rapidly throughout the device prior to collapse of the scaffold. This increased rate of cell migration was done using chemotactic ground substances such as hyaluronic acid, cell seeding or biologics. All this served to do was to spread out the cell population and reduce the rate of hyaline cartilage tissue formation, and as a result, biased any new tissue growth of cartilage towards the fibrocartilage lineage. Although some success in establishing hyaline cartilage can be seen in small defects of 5 millimeters or less, larger defects show tell tale signs of collapse or dimpling in the center of a repair plug, as the less desirable fibrocartilage, which has grown within the prior art devices, succumbs to the forces within the joint. Additionally, prior art devices show a halo or ring of collapsed tissue around the periphery of the device do to lack of intimate contact with the uninvolved tissue that has retracted away from the defect site.
Another discovery of applicants is that prior art devices do not address the instantaneous articular cartilage tissue contraction that occurs when the surface of hyaline cartilage is cut or torn. Upon damage, the cartilage retracts way from the defect site forming a funnel. Thus prior art devices, upon implantation, do not make contact with the surrounding uninvolved cartilage.
The uninvolved host tissue, that is, the normal tissue adjacent to and surrounding the defect site that is not involved with the defect, is able to influence the activities of cells that migrate into and establish themselves at the periphery of a scaffold placed into the defect. The cells of the uninvolved tissue, along with the extracellular matrix of the uninvolved host tissue adjacent to the periphery of the implanted scaffold are already established as hyaline cartilage and thus mechanically and chemically react to stresses appropriately. Through a process, sometimes referred to as mechanical signal transduction, the established host tissue is able to influence the phenotype and extracellular matrix produced by the adjacent cells in the scaffold thus producing the desired hyaline cartilage. Specifically, cartilaginous tissues perform specialized functions under normal physiological conditions. Anomalous mechanical loading of these tissues often leads to pathology. For example, the lack of mechanical stimulation of a joint leads to suppression of proteoglycan synthesis and release of mediators responsible for degradation of cartilage matrix components. This is believed to be the cause of collapse or dimpling of the newly formed cartilage seen with prior art devices.
The molecular mechanisms controlling the response of cartilaginous tissues to their mechanical environment are not completely understood. Furthermore, there is a dearth of knowledge about the modes of mechanical signal transduction in chondrocytes. Several theories concerning the molecular mechanisms through which mechanical stimuli modulate the expression of cartilage extracellular matrix (ECM) components have been proposed, some of which are: 1) receptor mediated cell-ECM adhesion contributes to the transduction of mechanical signals in chondrocytes, 2) mechanical signal transduction in chondrocytes requires activation of the phosphoinositol and/or cyclic AMP (also known as Cyclic adenosine monophosphate or cAMP) signaling pathways, and 3) mechanical stimulation of the expression of aggrecan is mediated through activation of specific cis-acting elements of the promoter and/or UTRs (untranslated regions) of the aggrecan gene. No matter the specific mechanism through which it happens, applicants believe that the influence uninvolved host tissue has over the cells in the scaffold matrix extends approximately 2.5 millimeters. Thus, this places a limit of success for prior art devices having a matrix equal to, or less stiff than the surrounding host tissue to 5 millimeters in diameter. However, any device having a cartilage scaffold matrix greater in stiffness than the surrounding host tissue will not be properly influenced by mechanical signal transduction and will either form calcified tissues or disorganized fibrocartilage that collapses as the matrix degrades and the tissue experiences stress loading.
In order to prevent the observed central collapse or dimpling within the cartilage layer of prior art implants, applicants have discovered that a new type of scaffold must be made that retards rapid migration of cells across the entire diameter of the device, thereby concentrating cells and cell activity at the edges of the device, promoting rapid and systematic tissue conduction and maturation, moving from the outer edge of the device towards the interior. Additionally, the area within the cartilage region of the scaffold where cell activity is occurring must be less rigid than the surrounding uninvolved tissue, to ensure that it is subject to the mechanical influences of the adjacent uninvolved tissue.
Within the bone layer, known prior art devices failed to recognize the impact a rigid scaffold has on the surrounding uninvolved tissue. Whereas malleable elastic scaffolds (scaffolds that can be deformed and then return to their original shape) are desirable for the cartilage layer, rigid stable scaffolds (scaffolds that resist deformation) are required for proper migration and attachment of bone forming cells. However, nearly the opposite conditions are required for stability of existing bone, as micromotion is beneficial to healthy bone structure. Micro-motion and/or stresses are necessary to keep healthy bone from becoming osteopenic. Osteopenia refers to bone mineral density that is lower than normal. Bone mineral density has been shown to drop in healthy individuals who are bedridden, as well as in astronauts who have reduced stress on their skeletal system due to the effects of reduced gravity while in space. As this occurs, the bones lose minerals, heaviness (mass), and structure, making them weaker and increasing their risk of collapse and or breaking. Localized bone mineral density loss has been witnessed due to stress shielding caused by orthopedic rods and plates. During repair of damaged cartilage with prior art devices, voids and osteopenic zones have been observed to form below implanted tissue scaffolds. The theory behind this pathology formation is that stress shielding, caused by the presence of porous tissue scaffolds, results in bone density loss. The scaffolds dampen vibrations that would normally be transferred through the malleable elastic articular cartilage to the calcified region and then conducted deeper into the bone. These conductive forces are necessary for normal bone biology. The conducted forces in normal bone located below an articulating joint travel not only through the bone trabecula, but also through the viscous gel of bone marrow surrounding the bone trabecula. This is because the bone trabecula located under the cartilage of a joint shows a general histologic pattern of elongated channels radiating out from the calcified region into the subchondral bone. Thus forces are not only transmitted down the rigid walls of the channels formed by the trabecula, but are also transmitted by the gelatinous bone marrow contained within the channels. Two functional problems identified with rigid porous scaffolds of prior art devices are as follows. First these rigid devices do not contain elongated channels and thus they tend to dissipate and dampen the hydrostatic pressure pulses that would normally flow through viscous fluids. Secondly these devices are too rigid through the cartilage region thus not allowing for initial compression to establish a pressure wave through the bone marrow.
In order to prevent undesirable bone voids from forming in uninvolved tissues adjacent to the repair device, what is needed is a scaffold capable of transferring forces through the device, and into the tissue. This deep bone mechanical stimulation is due to compression of the articular cartilage region generating mechanical and fluidic forces during normal movement in the joint.
Concerning the synovial fluid, prior art devices fail to recognize the role this substance plays in maintaining healthy articular cartilage. Synovial fluid is a thick, stringy fluid found in the cavities of synovial joints. Synovial fluid reduces friction between the articular cartilage surfaces as well as providing cushioning during movement. The inner membrane of synovial joints is called the synovial membrane and it secretes synovial fluid into the joint cavity. This fluid forms a thin layer (about 50 microns thick) at the surface of cartilage and seeps into the micro-cavities and irregularities in the articular cartilage surface, filling all empty space thus presenting a uniform, smooth surface. The fluid in the articular cartilage effectively serves as a synovial fluid reserve, during movement; the synovial fluid held in the cartilage is squeezed out mechanically to maintain a layer of fluid on the cartilage surface. This so called weeping lubrication ensures that increased friction does not occur as some of the lubrication fluid is swept away during joint movement.
Synovial tissue is composed of vascularized connective tissue that lacks a basement membrane. Two cell types (type A and type B) are present: Type B cells produce synovial fluid. Synovial fluid is made of hyaluronic acid and lubricin, proteinases, and collagenases. Synovial fluid exhibits non-Newtonian flow characteristics. The viscosity coefficient is not a constant, the fluid is not linearly viscous, and its viscosity increases as the shear rate decreases.
Almost all of the protein constituents of synovial fluid are derived from plasma. The passage of plasma proteins to synovial fluid is related to the size and shape of the protein molecule. Most proteins with molecular weights less than 100,000 daltons are readily transferred from one fluid space to another. Thus synovial fluid is a plasma dialysate modified by constituents secreted by the joint tissues. The major difference between synovial fluid and other body fluids derived from plasma is the high content of hyaluronic acid (mucin) in synovial fluid. Normal synovial fluid contains 3-4 mg/ml hyaluronan (hyaluronic acid), a polymer of nonsulfated polysaccharides composed of D-glucuronic acid and D-N-acetylglucosamine joined by alternating beta-1,4 and beta-1,3 glycosidic bonds. Hyaluronan is synthesized by the synovial membrane and secreted into the joint cavity to increase the viscosity and elasticity of articular cartilage and lubricates the surfaces between synovium and cartilage. Both fibroblasts beneath the synovial membrane intima and synovial membrane-lining cells produce this mucopolysaccharide constituent of synovial fluid.
Synovial fluid is believed to have two main functions: to aid in the nutrition of articular cartilage by acting as a transport medium for nutritional substances, such as glucose, and to aid in the mechanical function of joints by lubricating the articulating surfaces. Articular cartilage has no blood, nerve, or lymphatic supply. Glucose for articular cartilage chondrocyte energy is transported from the periarticular vasculature to the cartilage by the synovial fluid. Synovial fluid contains lubricin secreted by synovial cells. Synovial fluid is chiefly responsible for so-called boundary-layer lubrication, which reduces friction between opposing surfaces of cartilage. There is also some evidence that synovial fluid helps regulate synovial cell growth. Synovial fluid serves many functions including: reducing friction by lubricating the joint; absorbing shocks; and supplying oxygen and nutrients to, as well as removing carbon dioxide and metabolic wastes from, the chondrocytes within articular cartilage.
Normal synovial fluid does not clot but may exhibit thixotropy, the property of certain gels to become fluid when exposed to shear forces such as shaking. On standing at room temperature, normal synovial fluid may assume gelatin-like appearance, characterized by higher viscosities. When shaken it will assume a normal fluid nature. Many enzymes have been found in the normal synovial fluid. Alkaline phosphatase, acid phosphatase, lactic dehydrogenase, and other enzymes are present in detectable quantities. Enzymes enter the synovial fluid directly from the plasma or may be produced locally by the synovial membrane or released by synovial fluid macrophages. Synovial fluid also contains phagocytic cells that remove microbes and the debris that results from normal wear and tear in the joint.
Some prior art devices utilize fluid impermeable layers at the cartilage surface, the bone/cartilage interface, or both locations, or have rigid articular cartilage regions resistant to receiving fluid from the synovial space. These types of structures serve as barriers that prevent the normal transfer of essential elements from the synovial fluid, into and out of the cartilage region. What is needed is a device capable of facilitating joint fluid therapy to the chondrocytes within the defect. Joint fluid therapy encompasses delivering, receiving, accumulating and controlling the location of desirable factors or molecules present in the synovial fluid while also delaying or preventing destructive factors, such as digestive enzymes, from prematurely degrading the matrix. These desirable factors or molecules can be those naturally occurring within the synovial fluid or biologically active agents administered into the synovial fluid.